{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T12:31:09Z","timestamp":1766493069201,"version":"build-2065373602"},"reference-count":26,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T00:00:00Z","timestamp":1693526400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shanghai Committee of Science and Technology of China","award":["23ZR1407800","20214Y0441"],"award-info":[{"award-number":["23ZR1407800","20214Y0441"]}]},{"name":"Research Project of Shanghai Municipal Health Commission","award":["23ZR1407800","20214Y0441"],"award-info":[{"award-number":["23ZR1407800","20214Y0441"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Neurodevelopmental disorders (NDDs) are a group of high-incidence rare diseases with genetic heterogeneity. PPP2R1A, the regulatory subunit of protein phosphatase 2A, is a recently discovered gene associated with NDDs. Whole\/clinical exome sequencing was performed in five patients with a family with NDDs. In vitro experiments were performed to evaluate the mutants\u2019 expression and interactions with the complex. The genotype\u2013phenotype correlations of reported cases as well as our patients with PPP2R1A variants were reviewed. We reported five unrelated individuals with PPP2R1A variants, including two novel missense variants and one frameshift variant. The protein expression of the Arg498Leu variant was less than that of the wild-type protein, the frameshift variant Asn282Argfs*14 was not decreased but truncated, and these two variants impaired the interactions with endogenous PPP25RD and PPP2CA. Furthermore, we found that pathogenic variants clustered in HEAT repeats V, VI and VII, and patients with the Met180Val\/Thr variants had macrocephaly, severe ID and hypotonia, but no epilepsy, whereas those with Arg258 amino acid changes had microcephaly, while a few had epilepsy or feeding problems. In this study, we reported five NDD patients with PPP2R1A gene variants and expanded PPP2R1A pathogenic variant spectrum. The genotype and phenotype association findings provide reminders regarding the prognostication and evidence for genetic counseling.<\/jats:p>","DOI":"10.3390\/genes14091750","type":"journal-article","created":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T08:19:39Z","timestamp":1693556379000},"page":"1750","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Novel Variants of PPP2R1A in Catalytic Subunit Binding Domain and Genotype\u2013Phenotype Analysis in Neurodevelopmentally Delayed Patients"],"prefix":"10.3390","volume":"14","author":[{"given":"Yanyan","family":"Qian","sequence":"first","affiliation":[{"name":"Center for Molecular Medicine, Pediatrics Research Institute, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, 399 Wanyuan Road, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yinmo","family":"Jiang","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Pediatrics Research Institute, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, 399 Wanyuan Road, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji","family":"Wang","sequence":"additional","affiliation":[{"name":"Neurology Department, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, 399 Wanyuan Road, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Pediatrics Research Institute, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, 399 Wanyuan Road, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingbing","family":"Wu","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Pediatrics Research Institute, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, 399 Wanyuan Road, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanfeng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Neurology Department, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, 399 Wanyuan Road, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiu","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Child Health Care, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, 399 Wanyuan Road, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huijun","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Pediatrics Research Institute, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, 399 Wanyuan Road, Shanghai 201102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1056\/NEJMoa2035790","article-title":"100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care\u2014Preliminary Report","volume":"385","author":"Investigators","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1042\/BST20201313","article-title":"Protein Phosphatase 2A (PP2A) mutations in brain function, development, and neurologic disease","volume":"49","author":"Verbinnen","year":"2021","journal-title":"Biochem. Soc. Trans."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.clim.2017.07.012","article-title":"The serine\/threonine protein phosphatase 2A controls autoimmunity","volume":"186","author":"Sharabi","year":"2018","journal-title":"Clin. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"jcs248187","DOI":"10.1242\/jcs.248187","article-title":"Protein phosphatase 2A\u2014Structure, function and role in neurodevelopmental disorders","volume":"134","author":"Sandal","year":"2021","journal-title":"J. Cell Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7297","DOI":"10.1038\/s41467-021-27620-x","article-title":"Protein phosphatase 2A inactivation induces microsatellite instability, neoantigen production and immune response","volume":"12","author":"Yen","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_6","first-page":"2277","article-title":"To be or not to be: PP2A as a dual player in CNS functions, its role in neurodegeneration, and its interaction with brain insulin signaling","volume":"76","author":"Javadpour","year":"2019","journal-title":"Cell Mol. Life Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3051","DOI":"10.1172\/JCI79860","article-title":"B56delta-related protein phosphatase 2A dysfunction identified in patients with intellectual disability","volume":"125","author":"Houge","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4775","DOI":"10.1093\/hmg\/ddv182","article-title":"Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth","volume":"24","author":"Loveday","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.ajhg.2018.12.002","article-title":"De Novo Mutations Affecting the Catalytic Calpha Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders","volume":"104","author":"Reynhout","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/s41436-020-00981-2","article-title":"The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction","volume":"23","author":"Lenaerts","year":"2021","journal-title":"Genet. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1136\/jmg-2022-108713","article-title":"Clinical, neuroimaging and molecular characteristics of PPP2R5D-related neurodevelopmental disorders: An expanded series with functional characterisation and genotype-phenotype analysis","volume":"60","author":"Oyama","year":"2023","journal-title":"J. Med. Genet."},{"key":"ref_12","unstructured":"Adam, M.P., Everman, D.B., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., and Amemiya, A. (1993). GeneReviews((R)), University of Washington."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1055\/s-0039-1692414","article-title":"A Newborn with Severe Ventriculomegaly: Expanding the PPP2R1A Gene Mutation Phenotype","volume":"8","author":"Wallace","year":"2019","journal-title":"J. Pediatr. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3262","DOI":"10.1002\/ajmg.a.62946","article-title":"PPP2R1A neurodevelopmental disorder is associated with congenital heart defects","volume":"188","author":"Baker","year":"2022","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Lei, T., Zhen, L., Yang, X., Pan, M., Fu, F., Han, J., Li, L., Li, D., and Liao, C. (2023). Prenatal Diagnosis of PPP2R1A-Related Neurodevelopmental Disorders Using Whole Exome Sequencing: Clinical Report and Review of Literature. Genes, 14.","DOI":"10.3390\/genes14010126"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1042\/bj3530417","article-title":"Protein phosphatase 2A: A highly regulated family of serine\/threonine phosphatases implicated in cell growth and signalling","volume":"353","author":"Janssens","year":"2001","journal-title":"Biochem. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"127624","DOI":"10.1016\/j.jhazmat.2021.127624","article-title":"PP2A-mTOR-p70S6K\/4E-BP1 axis regulates M1 polarization of pulmonary macrophages and promotes ambient particulate matter induced mouse lung injury","volume":"424 Pt C","author":"Chen","year":"2022","journal-title":"J. Hazard. Mater."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5719","DOI":"10.1158\/0008-5472.CAN-15-3342","article-title":"Recurrent PPP2R1A Mutations in Uterine Cancer Act through a Dominant-Negative Mechanism to Promote Malignant Cell Growth","volume":"76","author":"Haesen","year":"2016","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1136\/jmedgenet-2021-108354","article-title":"Genetic architecture in neonatal intensive care unit patients with congenital heart defects: A retrospective study from the China Neonatal Genomes Project","volume":"60","author":"Wang","year":"2023","journal-title":"J. Med. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s10048-015-0466-9","article-title":"De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism","volume":"17","author":"Shang","year":"2016","journal-title":"Neurogenetics"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Biswas, D., Cary, W., and Nolta, J.A. (2020). PPP2R5D-Related Intellectual Disability and Neurodevelopmental Delay: A Review of the Current Understanding of the Genetics and Biochemical Basis of the Disorder. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041286"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"a006135","DOI":"10.1101\/mcs.a006135","article-title":"Somatic variation as an incidental finding in the pediatric next-generation sequencing era","volume":"7","author":"Melas","year":"2021","journal-title":"Cold Spring Harb. Mol. Case Stud."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.biocel.2017.12.015","article-title":"Protein phosphatase 2ACalpha gene knock-out results in cortical atrophy through activating hippo cascade in neuronal progenitor cells","volume":"95","author":"Liu","year":"2018","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1038\/ng.2331","article-title":"De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes","volume":"44","author":"Riviere","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1007\/s42000-021-00287-1","article-title":"Hypoglycemia due to PI3K\/AKT\/mTOR signaling pathway defects: Two novel cases and review of the literature","volume":"20","author":"Maines","year":"2021","journal-title":"Hormones"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ajhg.2012.10.021","article-title":"Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes","volume":"92","author":"Orloff","year":"2013","journal-title":"Am. J. Hum. Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/9\/1750\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:45:00Z","timestamp":1760129100000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/9\/1750"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,1]]},"references-count":26,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["genes14091750"],"URL":"https:\/\/doi.org\/10.3390\/genes14091750","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2023,9,1]]}}}